AAV-mediated gene transfer of a checkpoint inhibitor in combination with HER2-targeted CAR-NK cells as experimental therapy for glioblastoma.

Glioblastoma (GB) is the most common primary brain tumor, which is characterized by low immunogenicity of tumor cells and prevalent immunosuppression in the tumor microenvironment (TME). Targeted local combination immunotherapy is a promising strategy to overcome these obstacles. Here, we evaluated tumor-cell specific delivery of an anti-PD-1 immunoadhesin (aPD-1) via a targeted adeno-associated viral vector (AAV) as well as HER2-specific NK-92/5.28.z (anti-HER2.CAR/NK-92) cells as components for a combination immunotherapy. In co-culture experiments, target-activated anti-HER2.CAR/NK-92 cells modified surrounding tumor cells and bystander immune cells by triggering the release of inflammatory cytokines and upregulation of PD-L1. Tumor cell-specific delivery of aPD-1 was achieved by displaying a HER2-specific designed ankyrin repeat protein (DARPin) on the AAV surface. HER2-AAV mediated gene transfer into GB cells correlated with HER2 expression levels, without inducing anti-viral responses in transduced cells. Furthermore, AAV-transduction did not interfere with anti-HER2.CAR/NK-92 cell-mediated tumor cell lysis. After selective transduction of HER2+ cells, aPD-1 expression was detected at the mRNA and protein level. The aPD-1 immunoadhesin was secreted in a time-dependent manner, bound its target on PD-1-expressing cells and was able to re-activate T cells by efficiently disrupting the PD-1/PD-L1 axis. Moreover, high intratumoral and low systemic aPD-1 concentrations were achieved following local injection of HER2-AAV into orthotopic tumor grafts in vivo. aPD-1 was selectively produced in tumor tissue and could be detected up to 10 days after a single HER2-AAV injection. In subcutaneous GL261-HER2 and Tu2449-HER2 immunocompetent mouse models, administration of the combination therapy significantly prolonged survival, including complete tumor control in several animals in the GL261-HER2 model. In summary, local therapy with aPD-1 encoding HER2-AAVs in combination with anti-HER2.CAR/NK-92 cells may be a promising novel strategy for GB immunotherapy with the potential to enhance efficacy and reduce systemic side effects of immune-checkpoint inhibitors.

The incidence of fragility hip fractures in a subpopulation of South Africa.

BACKGROUND: Fragility hip fractures (FHFs) are associated with significant morbidity, mortality and burden on the healthcare system. European and North American literature suggests that the worldwide incidence of FHFs is increasing, but very little is known about the incidence of FHFs in Africa and South Africa (SA). Historically FHFs were believed to be uncommon in black African populations, but recent studies have shown a marked increase in the incidence compared with the early literature. OBJECTIVES: To investigate the age-, gender- and population group-specific incidences of FHFs in a subpopulation in Eastern Cape Province, SA. METHODS: A retrospective review of all patients presenting with FHFs was performed at a tertiary hospital in the Eastern Cape over a 1-year period. Age-, gender- and population group-specific incidence rates were calculated for 5-year age intervals using the age distribution data of the western region of the Eastern Cape (WREC) as a denominator for each age group. Overall crude incidence rates were calculated by using the sum total of FHFs, divided by the study population. All incidences were calculated as number of fractures per 100 000 people annually. RESULTS: A total of 253 patients with FHFs were included. The crude incidence rate of low-energy hip fractures in the WREC was 19.3 per 100 000 (males 14.6, females 23.4) over the study period. Population group-specific incidences were 15.1, 18.7, 19.9 and 46.6 per 100 000 for black, coloured, Indian and white population groups, respectively. The highest number of low-energy hip fractures in females occurred in the ≥85-year (19.6%) and 70 - 74-year (16.5%) age groups, with the highest number of male cases observed in the 60 - 64-year group (20.2%). The highest frequency distribution of FHFs was observed in black males aged 60 - 64 years (5.5%; n=14) and black females aged 70 - 74 years (6.3%; n=16). CONCLUSIONS: The local incidence of FHFs is higher than initially reported, but when compared with other countries remains on the lower end of spectrum. A large proportion of FHFs are occurring in young patients (<65 years). These findings warrant further investigation that may prompt the development of preventive strategies and optimal treatment programmes.

Prevalence of a postoperative troponin leak in patients with cardiac risk factors undergoing knee and hip arthroplasty in a South African population.

BACKGROUND: Patients undergoing arthroplasty may have comorbidities that put them at risk of myocardial injury after non-cardiac surgery (MINS). MINS, a new clinical concept that has a different pathophysiology from conventional myocardial infarction, is related to a supply-demand mismatch ischaemia in the perioperative setting. MINS is often a silent event, and the diagnosis relies on cardiac biomarker testing such as troponin T. The incidence is estimated at 40%, with a fourfold increase in morbidity and mortality risk 1 year post surgery. OBJECTIVES: To determine the prevalence of postoperative troponin leak in a single-centre arthroplasty unit in patients with various cardiac risk factors undergoing hip or knee arthroplasty and investigate the differences in troponin T levels between comorbidities and different types of arthroplasty, i.e. total hip replacement (THR), total knee replacement (TKR) and neck of femur (NoF) fracture hip replacement. METHODS: A prospective, cross-sectional study of patients with one or more cardiac risk factors undergoing replacement surgery was conducted from October 2017 to April 2018. Troponin levels of all included patients were recorded on days 1 and 3 post surgery using a high-sensitivity cardiac troponin T assay (Roche hs-cTnT). A level of >15 ng/L is considered abnormal and termed a positive troponin leak, while >100 ng/L is considered suspected acute coronary syndrome (ACS). RESULTS: One hundred and sixty patients (n=66 THR, n=55 NoF hip replacement, n=39 TKR) were included. Sixty-eight patients (42%) had a positive troponin leak, and in 6 of these cases ACS was suspected. The highest prevalence of troponin leak was recorded in patients undergoing NoF hip replacement (62%), followed by TKR (46%) and then THR (24%). Sixty-two patients (38%) had positive troponin levels on day 1 and 53 patients (33%) had positive levels on day 3. Important patient cardiac risk factors were identified in the presence of a positive troponin leak, with ischaemic heart disease, hypertension, diabetes, renal disease, age >65 years and atrial fibrillation being statistically most likely. CONCLUSIONS: Postoperative troponin surveillance is an inexpensive and reliable way to identify patients at risk of MINS and subsequently enhance early detection, medical optimisation and referral strategies. Simple interventions may improve outcomes and contribute to lower ACS rates and the timeous prevention of other complications. The prevalence of MINS in orthopaedic-specific patients in South Africa (SA) and other resource-constrained developing countries is unknown. Our finding of 42% positive troponin leaks raises awareness of this issue, and we recommend routine postoperative troponin surveillance for all arthroplasty units in SA.

Intramedullary fixation versus anatomically contoured plating of unstable ankle fractures: a randomized control trial.

AIM: This study compared functional outcomes between anatomical shaped fibular plates and intramedullary nail fixation of adult patients who sustained unstable ankle fractures. METHODS: A prospective randomized control trial was conducted between November 2013 and December 2016 on patients that presented with an unstable ankle fractures. They were randomized into a plate-and-screw group and a fibula nail group. At each post-operative visit the wounds were reviewed, and specific outcome measures were recorded, which included (i) the patient reported outcome measure (PROM) Olerud and Molander functional score, (ii) the Grimby score, (iii) swelling around the malleoli, (iv) plantar flexion, (v) dorsiflexion, (vi) inversion, and (vi) eversion. RESULTS: Significant differences were observed in scar size (p < 0.001) and screening time (p < 0.001) whilst no differences were observed in functional and PROM measures. Although not statistically significant, of clinical value is one deep infection that occurred in the plate group, whilst no infections occurred in the nail group. CONCLUSION: Both fixation methods yielded very similar functional results with differences only in scar size, screening time and swelling. Although none of these warrant a change in surgical decision-making processes, taken together, these factors potentially influence the decisions made in terms of surgical modalities used.

Lost to follow-up: Challenges to conducting orthopaedic research in South Africa.

Loss to follow-up poses a major problem for clinicians and researchers, and several factors that may increase its risk have been postulated. The objective of this study was to describe potential factors that contribute to loss to follow-up as seen in orthopaedic patients participating in a research study and attending the sole public orthopaedic service provider in the Northern Cape Province of South Africa (SA). All patients who underwent ankle fracture surgery at Kimberley Provincial Hospital between January 2012 and July 2013 were included, and the number of follow-up visits attended by each participant was recorded prospectively. Demographic information pertaining to travel distance, social circumstances and comorbid conditions was captured and reviewed. A total of 268 patients (male n=112, 41.8% and female n=156, 58.2%) were included. The mean (standard deviation (SD)) age was 42.3 (13.8) years (95% confidence interval (CI) 40.6 - 43.9, n=266) and the mean body mass index (BMI, kg/m2) was 28.0 (6.5) (95% CI 27.2 - 28.8, n=251), the BMI for females being 30.2 (6.1) (95% CI 29.3 - 31.2, n=152) compared with 24.6 (5.7) (95% CI 23.4 - 25.7, n=99) for males. After excluding local patients living within 5 km of the hospital (n=77), the mean travel distance was 460 km (range 10 - 910). There was a significant association between the number of follow-up visits attended and travel distance (incidence rate ratio (IRR) 0.999, 95% CI 0.999 - 1.000; p=0.030), BMI (IRR 0.980, 95% CI 0.966 - 0.994; p=0.004) and HIV status (IRR 0.841, 95% CI 0.725 - 0.975; p=0.022). The main factors identified in this study that influenced the number of follow-up visits attended were travel distance, BMI and HIV status. BMI was a unique finding in our study. It was identified to be a significant contributing factor to the loss to follow-up. BMI was not a contributing factor in other studies.

PAX2 is an antiapoptotic molecule with deregulated expression in medulloblastoma.

PAX2 is a paired box transcription factor possessing a fundamental role in the embryogenesis of hindbrain and urinary tract. PAX genes are proto-oncogenes, PAX2 expression may contribute to the pathogenesis of renal cell carcinoma. Because of the expression of PAX2 in the developing hindbrain and its essential role in cerebellar development, it has been hypothesized that PAX2 may also be involved in medulloblastoma tumorigenesis. We investigated the expression pattern of PAX2 and various genes of the neuronal lineage in medulloblastoma and glioma cell lines. We found high expression of PAX2 mRNA and PAX2 protein in medulloblastoma cells and some glioma cell lines independent of their neuronal lineage gene expression signature. Gene suppression of PAX2 decreased the expression of the PAX2 transcriptional target GDNF in Daoy cells and had a profound cytotoxic effect in vitro on Daoy medulloblastoma and T98G glioma cells. Expression of PAX2 was then assessed in two separate medulloblastoma tissue microarrays with a total of 61 patient samples by immunohistochemistry. PAX2 expression was detected in the majority of medulloblastoma samples and correlated with less differentiated histology. Therefore, PAX2 is a biomarker for a more aggressive medulloblastoma phenotype and may represent a novel therapeutic target.

Induction of feline immunodeficiency virus specific antibodies in cats with an attenuated Salmonella strain expressing the Gag protein.

Salmonella typhimurium aroA strains (SL3261), expressing high levels of the Gag protein of feline immunodeficiency virus (FIV) fused with maltose binding protein (SL3261-MFG), were constructed using an invertible promoter system that allows the stable expression of heterologous antigens at levels toxic for bacteria. A SL3261 strain expressing the B subunit of cholera toxin by a similar system (SL3261-CtxB) served as a control in FIV-immunization experiments. Cats immunized once orally or intraperitoneally with SL3261-MFG or SL3261-CtxB all developed serum antibodies to SL3261 lipopolysaccharide and against maltose binding protein or the B subunit of cholera toxin, respectively. Two intraperitoneal immunizations with SL3261-MFG also resulted in the development of Gag specific serum antibodies. Two oral immunizations with SL3261-MFG primed for a Gag specific response, which was demonstrated upon FIV challenge. All challenged cats became infected and no significant differences in viral loads were found between SL3261-MFG and SL3261-CtxB immunized cats.

Central auditory processing in Alzheimer's disease.

OBJECTIVE: This investigation was designed to determine whether people in the early to middle phases of Alzheimer's disease (AD) show impaired central auditory processing as compared with nondemented elderly. DESIGN: A peripheral and central auditory test battery was administered to 10 subjects diagnosed with mild-to-moderate AD based on a neuropsychological test battery and radiographic techniques, and a control group of 10 subjects with no evidence of dementia, matched for age, gender, and average degree of hearing loss. Immittance audiometry, pure-tone and speech audiometry, and otoacoustic emissions were recorded in all subjects. Central auditory assessment included the synthetic sentence identification with ipsilateral competing message, dichotic digits, dichotic sentence identification, pitch patterns, and duration patterns. RESULTS: Peripheral auditory status was statistically similar between subject groups. Neither average high frequency hearing sensitivity nor mean speech recognition ability was significantly different. However, a significant difference was noted between groups for average low frequency hearing sensitivity in the left ear (p < 0.05). Subjects with AD showed slightly poorer low frequency thresholds versus matched controls. Based on analysis of performance on each measure of the central auditory test battery, the AD group scored significantly lower than the matched control group on four of the five measures utilized. Differences for right versus left ear performance were found among AD subjects. CONCLUSIONS: Overall patterns in findings cannot be easily explained as artifacts of cognitive decline. Results support screening for central auditory dysfunction in the AD population, since impaired processing could influence psychiatric assessment of cognitive deficit as well as audiologic management of peripheral hearing loss in this population.

Nutritional effects of KT/V in children on peritoneal dialysis: are there benefits from larger dialysis doses?

Dialysis adequacy is monitored by urea kinetic modeling (UKM), in particular by calculation of KT/V (normalized whole body urea clearance) and PCRN (normalized protein catabolic rate). All children on peritoneal dialysis from our unit (7 children; mean age 7 years, 8 months) participated in our study (dialysis research program of the French Registry of Peritoneal Dialysis). Every month analysis of dialysate and urine collections and blood samples were compared to a 3-day diet survey to analyze the relations between doses of dialysis (KT/V) and nutrition [dietary protein intake (DPI) and caloric intake]. Calculated protein intake and DPI were also compared. Spearman correlation coefficients were used to assess the association between variables. KT/V values were spread over a wide range (0.8-2.8, mean 1.9). KT/V was positively (weakly) correlated to PCRN (p = 0.07, y = 0.24x + 1.08, r = 0.2), but not to DPI. No correlation could be found between PCRN and DPI, but doses of dialysis (KT/V) were positively correlated to caloric intake (p = 0.001, y = 28.97x + 13.66, r = 0.424). We assume that the correlation between KT/V and PCRN is not necessarily the reason, but only a calculation effect. On the contrary, the positive correlation between KT/V and caloric intake allows us to speculate that more efficient dialysis enhances appetite.

Effectiveness of an inpatient geriatric service in a university hospital.

OBJECTIVE: To assess the effectiveness of an acute interdisciplinary inpatient geriatric service in a university hospital. DESIGN: Prospective randomized control study. SETTING: Large urban university hospital. PATIENTS: 40 consecutive inpatients, randomized for inclusion on the geriatric service (study patients, n = 20) or to continue usual hospital care (control patients, n = 20) from among the geriatric consult population. MAIN OUTCOME MEASURES: Subjects were followed for changes in length of stay, hospital costs, diagnostic testing, pharmacy use, functional status, discharge disposition, and readmission within 30 days after hospitalization. RESULTS: Mean age of patients study 79.2 years (control 73.9 years). Sixty percent of study patients went home and 30% to nursing homes (control 20% home, 65% nursing homes) P = .03. Total length of stay mean 20.3 days study (control 32.7 days), length of stay after randomization mean 7.7 days study (control 11.2 days), mean overall hospital costs $23,906 study (control $45,189), and mean hospital costs after randomization study $4,671 (control $9,404) were not significantly different by F-tests due to wide variability. Laboratory use was reduced with mean 4.4 tests study (control 16.9) P = .01 and mean laboratory costs $263 study (control $828) P = .02. Functional ability improved (scale 1-7) with mean improvement study 0.8 (control 0.3) P = .09. Mean number of medications were lower in the study group by 30% P = .02; mean cost of medications at discharge was reduced with study $38 (control $112); and mean pharmacy charges after randomization decreased $462 study (control $1,268) P = .06. Readmission 30 days after discharge was not significantly different (study 21%, control 33%). CONCLUSIONS: An interdisciplinary acute geriatric service can be cost effective in providing care to elderly patients in a university hospital. It can improve outcomes measured by decreased laboratory and pharmacy usage, improved functional status, and discharge to a lesser level of care without increasing length of stay or early readmission after discharge.

Integrating substance abuse education in the medical student curriculum.

Physicians miss the diagnosis of substance abuse in significant numbers of patients, partly because of a lack of education about identifying and treating those patients. This article describes an attempt to integrate substance abuse into the curriculum of a traditionally organized medical school. Faculty selection, determination of the skills and knowledge needed, and methods for enriching the curriculum to include substance abuse are described. Problems encountered during the project, benefits of implementing the curriculum changes, and recommendations for other medical schools choosing to implement such a program also are provided.

Effects of nifedipine GITS and atenolol monotherapy on serum lipids, blood pressure, heart rate, and weight in mild to moderate hypertension.

Forty-nine patients, with ages ranging from eighteen to seventy years and with mild to moderate primary hypertension (sitting diastolic blood pressure of greater than or equal to 95 mmgH and less than or equal to 115 mmHg) were randomized into a twenty-one-week, double-blind, prospective study to determine the effects of monotherapy of nifedipine GITS (gastrointestinal therapeutic system) versus atenolol on serum lipids, lipid subfractions, apolipoproteins, (apo), and blood pressure (BP). Nifedipine GITS and atenolol significantly reduced blood pressure, but nifedipine GITS reduced sitting and standing systolic BP significantly more than atenolol (p = .001). Sitting and standing heart rate decreased significantly (p = 0.001) during atenolol therapy but did not change significantly during nifedipine GITS therapy. Atenolol increased weight (mean change + 2.2 lb; p = 0.011), but nifedipine GITS decreased weight (mean change - 2.4 lb; p = 0.07). Nifedipine GITS had a more favorable effect on the lipid profile. High density lipoprotein cholesterol (HDL-C) and HDL2 subfractions were increased significantly (p = .001) as were apo A1 (p = 0.037) and apo A2 (p = 0.025). Nifedipine GITS increased HDL3 (NS), reduced triglycerides (TG) (NS), and had no significant effect on total cholesterol (TC) low density lipoprotein cholesterol (LDL-C) and apo B. Atenolol significantly increased serum total cholesterol (p = 0.039) and HDL-C and HDL2 (p = 0.049 and 0.048 respectively). Atenolol increased TG (NS) and apo B (NS) with little change in apo A1 and apo A2. It is concluded that nifedipine GITS had equal or better antihypertensive efficacy than atenolol and had a more favorable effect on the lipid profile. These effects may offer advantages in reducing CHD risk.

Increased metacarpal bone mass following 18 months of slow-acting antirheumatic drugs for rheumatoid arthritis.

Osteoporosis in RA is mediated by numerous inflammatory substances. This study was undertaken to see if SAARD could modify the rate of metacarpal bone loss in RA. Combined cortical thickness (CCT) measured at the midshaft of the right second metacarpal was used to calculate bone mass (CA%) using a digitizer. Eighty-one subjects were studied, all of whom had at least three sets of hand X-rays, the last of which was approximately 18 months following initiation of SAARD therapy. There were 12 males and 69 females. The mean age at time of starting therapy was 51 (SD 12) years while the mean duration of disease at the time was 7.6 (SD 8) years. The mean time to referral for SAARD from the general clinic was 2.5 (SD 3) years. The percentage fall in bone mass prior to therapy was 2.51%/day compared to a gain of 0.6%/day after therapy (P less than 0.05). Forty-nine patients were aged over 50 years while 32 were 50 years or younger at the time of study. Comparison showed that in the pretreatment period, the rate of change in CCT and CA% was not significantly dependent age (P less than 0.1). During that therapy, the rate of change in CCT and CA% significantly different in the two age groups. Patients aged over 50 years continued to lose bone, but at a slower rate (P less than 0.05). Patients aged 50 years or less either stopped losing or gained metacarpal bone mass during the study period (P less than 0.005). The time to referral for SAARD and disease duration (comparable in the two age groups) did not have a significant effect on changes in CA% during therapy. Change in bone mass could be predicted by change in disease activity. We conclude that SAARD have a significant sparing effect on metacarpal osteoporosis in RA. This positive effect is masked by the overwhelming influence of age (and menopause) and could be missed. Metacarpal osteoporosis seems a pathophysiologically more useful measure of radiological change in RA than erosions or joint space narrowing.

Association of self-reported injury and alcohol consumption in medical outpatients.

OBJECTIVE: This study was designed to examine the association between minor injury and level of alcohol consumption among adult outpatients. DESIGN: Self-administered survey of alcohol use and level of injury in prior month. SETTING: Adult outpatients attending a university-based general internal medicine private practice. PATIENTS/PARTICIPANTS: During a four-month period, 1,011 patients aged 18-65 years were asked to complete questionnaires while waiting to see a physician. The 791 who completed all forms appropriately are included in this study. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The total number of drinks and the total number of injuries reported during the preceding month were calculated. Nondrinkers reported an average of 0.51 (SD = 1.18) injuries in the prior month; and drinkers, 0.92 (SD = 1.70) injuries. Minor injuries were reported more frequently by heavier alcohol consumers only among younger patients (RR = 1.88). There was no association between reported injury and alcohol consumption among patients over 50 years of age (RR = 0.90). CONCLUSIONS: Minor injury is associated with heavier alcohol consumption in younger patients attending a general medical practice, but not among older patients. Further research is needed to establish a causal relationship between alcohol drinking and minor injury.

Comparison of biomechanics platform measures of balance and videotaped measures of gait with a clinical mobility scale in elderly women.

Performance on the clinical mobility index developed by Tinetti (9) was compared with biomechanics platform measures of sway and videotaped measures of gait in a sample of 43 community-dwelling aged women. Area measures of sway, but not velocity, were associated with performance on the mobility index. When standing on one leg with eyes open, the correlation coefficients for radial area per second with the mobility indices ranged from -0.59 to -0.64 (p less than .001). Knee range of motion and stride length correlated with performance on the mobility index. Knee range of motion correlation coefficients ranged from 0.47 to 0.54 (p less than .001), whereas the range was 0.62 to 0.68 (p less than .001) for stride length. These data demonstrate that biomechanics platform measures of sway and videotaped measures of gait are associated with subject performance on a clinical mobility index and may themselves also be predictive of persons susceptible to falling.

Comparison of two morbilliviruses isolated from seals during outbreaks of distemper in north west Europe and Siberia.

Recently morbilliviruses were isolated from harbour seals (Phoca vitulina) in North West Europe (phocid distemper virus-1: PDV-1) and from Baikal seals (Phoca sibirica) in Siberia (phocid distemper virus-2: PDV-2) during outbreaks of severe disease which resembled distemper in dogs. PDV-1 and PDV-2 were passaged in SPF dogs, in which they caused distemper-like disease symptoms, and were subsequently passaged in Vero cells in which they caused cytopathic changes. PDV-1, PDV-2, and canine distemper virus (CDV) were compared with respect to their biological, morphological, physical, protein chemical, and antigenic properties. It was concluded that PDV-1 should be considered a newly recognized member of the genus Morbillivirus, whereas PDV-2 proved to be quite similar if not identical to CDV.

Deriving criteria for hearing impairment in the elderly: a functional approach.

We describe a method for deriving criteria for hearing impairment in the elderly based on self-reported handicap. Using the Sickness Impact Profile (SIP) and Hearing Handicap Inventory for the Elderly - Screening (HHIE-S) version as functional measures of handicap, the analysis proceeded in five steps: 1. Audiometric thresholds at various frequencies were inter-correlated. This was done both within and between ears. 2. Better and poorer ear thresholds were determined for each frequency, and these were correlated with the HHIE-S and SIP scores. 3. Using the HHIE-S and SIP scores as dependent variables, stepwise multiple linear regressions were used to select the frequencies that explained the most variance in the functional scales. 4. Using the HHIE-S and SIP as standards, receiver operating curves were constructed for each frequency to select the threshold level that provided the best test accuracy. 5. The newly-derived criteria were then compared against four other "traditional" criteria of hearing impairment. In general, the newly-derived criteria combined a relatively low frequency with a relatively high frequency, with the low frequency being functionally more important. Depending on the functional scale used, the threshold level was in the 25 to 35-dB range for the lower frequencies and 40 to 45-dB for the higher frequencies. These features provide a suitable compromise to the current debate over which threshold levels comprise the best discrimination of aged persons who are hearing-impaired. Future research should focus on developing consensus standards for functional hearing impairment and handicap in the elderly.

Comparing criteria of hearing impairment in the elderly: a functional approach.

We determined and compared the associations of four commonly used audiometric criteria of hearing impairment with two functional outcome measures in 152 aged persons screened in primary care medicine practices. The outcome measures were the Sickness Impact Profile (SIP, a measure of global function), and the Hearing Handicap Inventory for the Elderly-Screening Version (HHIE-S, a communication-specific measure of functional impairment). There were five main findings. (1) The four criteria of hearing loss were not independent. (2) The criterion of loss chosen depends on the functional measure of impairment. (3) Functional hearing impairment may also be classified by the number of criteria met. (4) A large subset (21%) of aged persons met one criterion but had little in the way of communicative or global dysfunction. (5) Hearing handicap as measured by the HHIE-S was directly associated with global dysfunction as measured by the SIP.

Derivation and validation of a prediction rule for identifying heavy consumers of alcohol.

Using two population-based cohorts of men aged 45-59, we sought to derive and validate a prediction rule for identifying heavy consumers of alcohol. Eighty-five percent of eligible men on electoral rolls in Caerphilly, Wales (derivation set, N = 2512) and 90% of eligible men on the practice lists of 16 Speedwell, England, general practitioners participated (validation set, N = 2348). Alcohol consumption was assessed by questionnaire with heavy alcohol consumption defined as the top 10% of the Caerphilly population's alcohol usage (greater than 525 cc ethanol per week). The prediction rule, Score = (mean corpuscular volume x 1.00) + (body mass index x 0.31) + (systolic blood pressure x 0.08) + HDL-cholesterol x 9.24) + (fasting triglyceride x 2.20) was derived by multiple linear regression in the Caerphilly cohort and validated in the Speedwell cohort. Comparing the lower 20% of the Score distribution with the upper 5%, likelihood ratios increased from 0.15 to 5.29 and 0.06 to 7.42 in the Caerphilly and Speedwell cohorts, respectively. Having a score of 136.30 or greater yielded a relative risk of being a heavy drinker of 23.1 (95% Cl = 10.1-53.0) in Caerphilly and 99.3 (95% Cl = 12.8-769.5) in Speedwell. The derived prediction rule is a valid diagnostic aid to help clinicians identify heavy alcohol consumers.